Since its initial discovery in 2000 by researchers in Japan, the hormone known as fibroblast growth factor-21 (FGF21) has intrigued biologists and endocrinologists. Mouse FGF21 is highly identical to human FGF21, making it useful for laboratory comparison.

It didn’t take long for investigators to realize FGF21 is a “novel therapeutic agent for human metabolism” in the regulation of sugar utilization, particularly in fat cells (adipocytes) in the liver. Therapeutic provision of FGF21 to laboratory mice reduces blood sugar levels and these animals are resistant to obesity. And FGF21 does not induce hypoglycemia (low blood sugar), cancer or weight gain at any tested dose in diabetic or healthy animals. Biologists were beginning to think of it as an ideal hormone/drug to treat diabetes.

The biological activity exhibited by FGF21 was found to be dependent upon a gene called Klotho that makes beta-klotho protein that in turn increases the ability of cell receptors for FGF21 to direct its beneficial effects upon fat cells in particular.

How it works

During periods of fasting, starvation or hibernation, cells must still produce energy or die. When food is withheld from animals for 12 hours or longer, liver cells produce FGF21. Researchers found that FGF21 switches the body to a fat-burning mode and allows the body to fuel itself with stored fat during times of food deprivation. FGF21 mobilizes lipids from fat cells and directs the liver to transform those energy-rich molecules to circulate throughout the body. Just the provision of FGF21 by itself produces the same biological responses as fasting without having to deprive calories.

Interest in FGF21 by drug companies ensued as pharmacologists began to make FGF21 look-alike molecules (analogs) in hopes of producing “superior metabolic” action. FGF21 could become the most advanced weapon against diet-induced diseases ever imagined.

These discoveries were very tantalizing for researchers. They didn’t want to jump to conclusions. They needed a lifespan study. Laboratory mice live about 12-18 months.

So researchers at University of Texas Southwestern Medical Center in Dallas launched a study to determine if in fact FGF21 will prolong the life of laboratory mice. Their efforts exceeded expectation. But their investigation also wiped the biological drawing board clean and forced biologists to re-think everything they have learned in the past decade.

Remarkably, genetically altering laboratory mice so they produce about 5-10 times more FGF2 during fasting resulted in a striking increase in lifespan without reducing food intake. These super-mice lived about 36% longer than normal mice and astoundingly better than 30% of the female mice in the study were still alive at 44 months of age when the study was finalized. The risk of death was reduced by 65% in male animals, 88% in females.

These animals apparently burned away their fat much more efficiently. The revved-up FGF21 mice were leaner than normal mice even though they ate about the same amount of food.

Surprising pathway

But all this was accomplished without activating other well-known longevity pathways (sirtuin genes, AMP kinase, mTOR and NAD+). Unexpectedly, calorie restriction, known to double the lifespan of laboratory animals by cutting caloric intake in half, did not trigger FGF21 hormone production.

Wow, it first appeared humanity was on the cusp of a giant breakthrough that could promote health and prolong life beyond any prior imagined mechanism. But there was one drawback. These FGF21 super-mice developed weak bones. Bone loss in these animals “may limit its utility as a therapeutic agent” the researchers disappointingly disclose.

Take-home message

So what is the take-home message of this discovery? What can modern longevity-seeking humans do to activate FGF21?

Fasting (breakfast skipping)

1. One life-prolonging practice might be to periodically fast. A 12-hour fast activates FGF21 which then begins to increase fat burning. There are some people who never eat breakfast, to prolong their daily fasting period. While most dieticians say skipping breakfast leads to overeating and obesity, almost all of the studies on this topic have been performed among growing children. Children are growing, not aging, and certainly don’t fit into the category of middle-agers who are experiencing mid-body weight gain.

Researchers in Japan report on a novel way to increase FGF21 hormone via the consumption of hydrogen-fortified drinking water. Mice given hydrogen water lost excessive weight experienced a decline in blood sugar, insulin and triglycerides, all which was correlated with an increase in FGF21. For the really serious pursuers of longevity, on the commercial side there is even a hydrogen drinking water produced in Malaysia that is touted for its health benefits.